2.1 Liver Cancer
In the United States, approximately 15,300 people (with a 2:1 male to female ratio) are diagnosed with liver cancer every year. Primary liver cancer is relatively rare in North America and Europe but poses a serious health problem worldwide. In contrast to an estimate of incidence in the U.S. of 3 per 100,000 population, the incidence in epidemic regions such as Africa and Asia varies from 30 per 100,000 to more than 100 per 100,000 population. (American Cancer Society, Cancer Facts and Figures, 1994, Atlanta, Ga.: American Cancer Society Inc.). Although primary liver cancer ranks low on the list of cancer incident in the U.S., it carries a grave prognosis with a fatality-to-case ratio of 0.8 (about 13,800 out of the 15,300 die from the disease in the U.S. each year.
Tumors of the liver may be benign or malignant, infant or adult. It is estimated from autopsy series that 1% to 7% of the population have some type of benign liver tumor (Henson et al., 1956, Surg Gynecol Obstet. 103:23–30). The most common benign liver tumor is the hemantioma, which is classified as hemangioendotheliomas, capillary hemangiomas, and caernous hemangiomas. They are believed to be sequestrations of primordial angioblastic cells. Hemangioendotheiiomas are generally found in infants and children, and approximately 50% of cases are associated with cutaneous vascular lesions. (Joyce et al., 1989, Prog Pediatr Surg. 22:69–93). Most are discovered within the first 6 months of life and may continue to enlarge.
On the other hand, there is adult primary liver cancer, which is a disease in which cancer (malignant) cells start to grow in the tissues of the liver. Primary liver cancer should be distinguished from metastatic cancer which originates in another organ (e.g., lung, breast, colon and rectum). When liver metastases occur at the time of initial diagnosis of the primary tumor, they are described as synchronous. If detected after the initial diagnosis, they are described as metachronous. The liver is a popular target for metastasis since it receives blood from the abdominal organs via the portal vein. Malignant cells detach from the primary cancer, by entering the bloodstream or lymphatic channels, travel to the liver, and grow independently.
Adult primary liver cancer is histologically classified into 5 groups: (1) hepatocellular carcinoma (liver cell carcinoma); (2) hepatocellular carcinoma (firbolamellar variant); (3) cholangiocarcinoma (intrahepatic bile duck carcinoma); (4) mixed hepatocellular cholangiocarcinoma; and (5) undifferentiated. Hepatocellular carcinoma is the most common primary malignant liver tumor, accounting for approximately 75% of liver cancers. Less common are cholangiocarcinomas which arise from the bile duct. As with any organ, rare tumors can also be found arising from other cellular components of the liver, including angiosarcoma. Other less frequently observed malignant liver tumors include fibrolamellar, cystadenoma, and epithelioid hemangioendothelioma.
The primary symptoms of hepatocellular carcinoma are those of a hepatic mass. Among patients with underlying cirrhotic disease, a progressive increase in alpha-fetoprotein (AFP) and/or in alkaline phosphatase or a rapid deterioration of hepatic function may be the only clue to the presence of the neoplasm. The biologic marker AFP is useful for the diagnosis of this neoplasm. By a radioimmunoassay technique, 50% to 70% of patients in the United States who have hepatocellular carcinoma have elevated levels of AFP. However, patients with other malignancies (germ cell carcinoma and, rarely, pancreatic and gastric carcinoma) also demonstrate elevated serum levels of this protein. (Stillwagon et al., 1991, Int'l J Rad Onc. Bio. Phys. 20(1):65–71; Izumi et al., 1992, Jof Surgical Oncology 49(3):151–55). Other prognostic variables include performance status, liver functions, and the presence or absence of cirrhosis and its severity in relation to the Child-Pugh classification. (Nakakura, 2000 Oncology (Huntington N.Y.) 14(7): 1085–1100). Infrequently, patients with this disease also have polycythemia, hypoglycemia, hypercalcemia, or dysfibrinogenemia.
There are several well known risk factors for liver cancer. Certain types of viral hepatitis, including chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), are associated with increased liver cancer risk. By far, hepatitis B infection (Blumberg et al., 1975, American Journal of Pathology 81(3):669–82) and hepatitis C infection (Tsukuma et al., 1993, New England J. Med. 328(25):1797–1801) appear to be the most significant causes of hepatocellular carcinoma, particularly in patients with continuing antigenemia and in those who have chronic active hepatitis. Scientists estimate that about 10–20 percent of people infected with HBV will develop liver cancer. There is evidence that patients with both hepatitis B and hepatitis C infection who consume more than 80 grams of alcohol per day have an increased risk of developing cancer (odds ratio of 7.3) when compared to patients who abstain from alcohol (Tagger et al., 1999, Int'l J. Cancer 81(5):695–99). Additionally, having a first-degree relative with hepatitis B plus hepatocellular carcinoma is associated with an increased risk (odds ratio 2.41) for family members who are hepatitis B carriers. (Yu et al., 2000, J. National Cancer Institute 92(14): 1159–64).
Long-term exposure to aflatoxins—a group of carcinogenic chemicals produced by a fungus found in tropical and subtropical regions that often contaminate peanuts, wheat, soy beans, corn and rice—can raise the risk of liver cancer (Alpert et al., 1971, Cancer 28(1):253–60). Occupational risks such as exposure to vinyl chloride before controls on vinyl chloride dust may cause sarcomas to develop in the liver, most commonly angiosarcoma. A history of other liver diseases, particularly cirrhosis of the liver, has been shown to increase the risk of liver cancer. Other risk factors include malnutrition, tobacco use, alcohol consumption, long-term use of anabolic steroids, birth control pills, and drinking water contaminated with arsenic.
Early stages of liver cancer can be asymptomatic and may go undetected for months or even years. The signs and symptoms of liver cancer do not become apparent until the disease has progressed to a late stage. Further, many of the symptoms are nonspecific. Liver cancer, both primary and metastatic, often exhibits symptoms of general malaise as well as pain and tenderness. Other signs include unexplained weight loss, persistent lack of appetite, fever of unknown origin, limb weakness, sensory loss, persistent abdominal pain, immature feeling of fullness, swelling of the abdominal are with or without breathing difficulties, sudden jaundice, and liver enlargement or a mass that can be felt in the liver area.
The staging of lung cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Treatment of liver cancer depends on the type of tumor and the stage of the disease, the condition of the liver, and the patient's age and overall health. The three main treatment methods include surgery, chemotherapy, and radiation therapy. Frequently, a combination of treatments is recommended.
However, surgical resection (the removal of a tumor) is the only way to cure liver cancer. Unfortunately, in the majority of liver cancers, complete removal of the cancer is not possible, either because the cancer has already spread beyond the liver or because the tumor is too large, or several tumors are present in different parts of the liver. Moreover, about 30% of hepatocellular carcinoma patients in the U.S. have cirrhosis. With cirrhosis, liver function is impaired, there is increased blood loss during surgery, especially in the presence of portal hypertension, and the liver lacks the normal capacity to regenerate. This makes removal of even a small amount of liver tissue at the perimeter of the cancer prohibitive, as it would not leave enough liver tissue to perform the essential functions of the organ.
There are two other surgical methods for destroying liver tumors without removing them. The first is called cryosurgery, in which the tumor is destroyed by freezing it was a metal probe. The second is called ethanol ablation, which involves injecting alcohol directly into the tumor to destroy the cancer cells. Nevertheless, recurrences may develop requiring nonsurgical therapy such as regional chemotherapy (by hepatic artery infusion), systemic chemotherapy (by vein or mouth), and external-beam radiation, often in combination.
The curative rate of liver cancer using radiation is extremely low and the side effects are undesirable. The proximity of radiosensitive tissues, including the liver, kidney, and duodenum, severely limits the efficacy of external-beam radiation therapy and has led to innovative approaches for delivering high-dose treatment, including precision high-dose external-beam techniques, interstitial or brachytherapy, and intraoperative and adjuvant radiation therapy. There is reported value for all these techniques, but because of the heterogeneity of patients, tumor size, stage of disease, performance status, and volume of the tumor, it is difficult to make a definitive conclusion concerning the superiority of one modality over the others. Titanium clips, which do not interfere with CT studies, can be surgically placed to mark the margins of the tumor, thus enabling the radiation therapist to design fields that will maximize tumor dosage and minimize injury to radiosensitive, normal adjacent structures (Dodelbower et al., 1984, World J Surg. 8:919–28).
Single agents such as 5-fluorouracil (5-FU) and doxorubicin are the most often used drugs in chemotherapy. Responses, however, are low (15% to 20%) and of short duration. Other active chemotherapeutic agents include Tomudex, Mitomycin C, and CPT-1. Today, combination chemotherapy is the standard. Studies show that using 5-FU in conjunction with doxorubicin (Adriamycin) results in a 13% response rate (Baker et al., 1977 Cancer Treat Rep. 61:1595–97). However, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents, hormone therapy, and radiation are useful in the treatment of liver cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.